In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

In the dopamine‐depleted striatum, extracellular signal‐regulated kinase (ERK) signaling is implicated in the development of l‐DOPA‐induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l‐DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D2 receptor (Drd2‐EGFP mice) or the dopamine D1 receptor (Drd1a‐EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6‐hydroxydopamine‐lesioned Drd2‐EGFP mice, l‐DOPA increased the phosphorylation of ERK, mitogen‐ and stress‐activated kinase 1 and histone H3, selectively in EGFP‐negative MSNs. Conversely, a complete co‐localization between EGFP and these phosphoproteins was observed in Drd1a‐EGFP mice. The effect of l‐DOPA was prevented by blockade of dopamine D1 receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l‐DOPA. Our results demonstrate that in the dopamine‐depleted striatum, l‐DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK‐dependent changes in striatal plasticity leading to dyskinesia.

Introduction: Tyrosine kinase inhibitors (TKIs) are an effective therapy for pts with CML. However, resistance to treatment driven by point mutations in the ABL kinase domain, particularly the T315I mutation, represents a clinical challenge. The T315I mutation confers resistance to all approved ATP-competitive TKIs except ponatinib (PON) and is associated with significantly worse clinical outcomes. PON use, however, is limited in many patients by its safety profile. Asciminib has a distinct mechanism of action and is the first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. Asciminib demonstrated clinical activity in heavily pretreated CML pts with or without mutations, with promising efficacy in pts with T315I, including those resistant to/intolerant of (R/I) PON. Methods: This phase 1 study enrolled adults with CML in chronic phase (CP) or accelerated phase (AP) R/I ≥ 2 TKIs; pts with T315I were eligible after receiving ≥ 1 TKI if no other effective therapy was available. Pts with uncontrolled cardiovascular conditions were excluded. Pts with T315I were assigned to varying dose levels in phase 1, and 200 mg twice daily (BID) was selected for cohort expansion. Here, we report updated efficacy and safety results in pts with T315I who received 200 mg BID (data cutoff: April 2, 2020). Results: A total of 52 pts with T315I received asciminib 200 mg BID. At the data cutoff, treatment was ongoing in 35/52 pts (67.3%); 17 (32.7%) discontinued treatment, a majority of whom (10 [19.2%]) discontinued due to physician's decision, mainly for unsatisfactory response (Table 1). Of pts still on treatment, 31/35 (88.6%) received treatment for > 48 wk. The median duration of exposure was 68.4 wk (range, 2-175 wk) and median dose intensity was 399.0 mg/day (range, 188-400 mg/day). Among evaluable pts not in major molecular response (MMR) at baseline, 23/49 (46.9%) achieved MMR and 21 of these responders were still in MMR at the time of data cutoff; 40.8%, 42.9%, 44.9%, and 46.9% had MMR by 24, 48, 72, and 96 wk, respectively. The Kaplan-Meier-estimated rate of durable first MMR among pts who achieved MMR was 87% (95% CI, 68.4-100.0) at 96 wk and remained unchanged until 144 wk. The median time to MMR was 12.1 wk (range, 4-84 wk). By 24 wk, 57.1% of PON-naive pts and 28.6% of PON-pretreated pts achieved MMR (Table 2). Three additional pts achieved MMR after 24 wk: 2 PON naive and 1 PON pretreated. The estimated cumulative MMR rate at 60 wk increased to 66% and 32% in PON-naive and PON-pretreated pts, respectively (Figure). Among 26 pts who did not achieve MMR, 3 had additional mutations (E255K, E355G, F359I) at baseline and 6 acquired new mutations after baseline (F359I [n = 2], A337T/F359V, M351T, M244V, E453Q). Among 2 pts who lost MMR, 1 acquired a new F359V mutation. Among evaluable pts without MMRat baseline, 13/49 (26.5%) and 10/49 (20.4%) achieved MR4 and MR4.5, respectively. Treatment-related adverse events (AEs) were reported in 45/52 pts (86.5%) and were mainly mild in severity; grade ≥ 3 AEs were reported in 17/52 pts (32.7%). All-grade serious AEs were reported in 12 pts (23.1%), with 2 (3.8%) deemed treatment related. No on-treatment deaths were reported. On-treatment AEs leading to discontinuation were reported in 4 pts (7.7%; disease progression, grade 2 thrombocytosis, grade 3 lipase elevation, and grade 4 pancytopenia, 1 pt each). Dose reductions and interruptions (excluding dosing errors) were reported in 21 (40.4%) and 22 (42.3%) pts, respectively (reduction and/or interruption in 29 pts total); they were mainly due to AEs (13 [25.0%] and 18 [34.6%] pts, respectively). The most frequent any-grade AEs of special interest (occurring in ≥ 10% of pts) were gastrointestinal toxicity (48.1%), hypersensitivity (26.9%), myelosuppression (25.0%), pancreatic toxicity (25.0%), hepatotoxicity (23.1%), thrombocytopenia (21.2%), hemorrhage (17.3%), leukopenia (15.4%), and edema and fluid retention (13.5%). Ischemic stroke and peripheral arterial occlusive disease were each reported in 1 pt; both pts had underlying cardiovascular disease. Conclusions: Asciminib 200 mg BID monotherapy continued to demonstrate a favorable safety profile and clinical efficacy in pts with CML-CP/AP harboring the T315I mutation, with durable MMR seen in almost half of the patients. Asciminib is a promising therapeutic option for pts with CML-CP/AP with T315I, including those for whom PON treatment has failed. Disclosures Cortes: Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Janssen:MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steegmann:Novartis: Honoraria, Other: Speaker; Bristol-Myers Squibb: Honoraria, Other: Speaker; Incyte: Honoraria, Other: Speaker; Pfizer: Honoraria, Other: Speaker. Heinrich:Novartis: Consultancy, Patents & Royalties: Patent on treatment of GIST licensed to Novartis; Blueprint Medicines: Consultancy; Deciphera: Consultancy, Speakers Bureau. Talpaz:IMAGO: Consultancy; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Etienne:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Deininger:Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fusion Pharma: Consultancy; Novartis: Consultancy, Other, Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC: Research Funding; Pfizer: Honoraria, Other, Research Funding; DisperSol: Consultancy; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ariad: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding. le Coutre:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Lang:Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Aimone:Novartis: Current Employment. Polydoros:Novartis: Current Employment, Current equity holder in publicly-traded company. Cacciatore:Novartis: Current Employment. Stenson:Novartis: Current Employment. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Asciminib is approved for patients with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10–200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

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